Linked Life Data

16318845

Source:http://linkedlifedata.com/resource/pubmed/id/16318845

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-12-26
pubmed:abstractText
Trivalent antimonial compounds (Sb(III)), originally used in the treatment of leishmaniasis, are now being proposed as a novel therapy for acute promyelocytic leukaemia (APL). Here, we examine the effects of Sb(III) and pentavalent antimonial drugs (Sb(V)) on glutathione homeostasis, oxidative stress and apoptosis in the human leukaemia monocyte cell line, THP-1. Although growth of THP-1 macrophages is unaffected by Sb(V), macrophages are extremely sensitive to Sb(III). On exposure to Sb(III), intracellular free glutathione (GSH) levels in macrophages decrease linearly by 50% over 4h, associated with efflux of both GSH and accumulation of intracellular glutathione disulphide (GSSG). Together these effects increase the redox potential of the GSSG/GSH couple from -282 to -225mV. Sb(III)-induced GSH efflux from THP-1 macrophages is accompanied by the concomitant efflux of Sb(III) at a constant molar ratio of 3 (GSH) to 1 (Sb(III)), respectively. Sb(III) directly inhibits glutathione reductase activity in macrophages, significantly retarding the regeneration of GSH from GSSG, following diamide oxidation. Sb(III)-treated THP-1 macrophages go on to exhibit elevated levels of reactive oxygen species and show the early signs of apoptosis. The absence of these effects in Sb(V)-treated THP-1 cells suggests that macrophages do not efficiently reduce Sb(V) to Sb(III). Collectively, these findings suggest that Sb(III) seriously compromises thiol homeostasis in THP-1 macrophages and that this may be an early defining event in the mode of action of antimonials against leukaemia cells.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0006-2952
pubmed:author
pubmed:issnType
Print
pubmed:day
12
pubmed:volume
71
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
257-67
pubmed:dateRevised
2007-8-13
pubmed:meshHeading
pubmed:year
2006
pubmed:articleTitle
Differential toxicity of antimonial compounds and their effects on glutathione homeostasis in a human leukaemia monocyte cell line.
pubmed:affiliation
Division of Biological Chemistry and Molecular Biology, Wellcome Trust Biocentre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH Scotland, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't